title: K⁺ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter.
abstract: The NLRP3 inflammasome is an important component of the innate immune system. However, its mechanism of activation remains largely unknown. We show that NLRP3 activators including bacterial pore-forming toxins, nigericin, ATP, and particulate matter caused mitochondrial perturbation or the opening of a large membrane pore, but this was not required for NLRP3 activation. Furthermore, reactive oxygen species generation or a change in cell volume was not necessary for NLRP3 activation. Instead, the only common activity induced by all NLRP3 agonists was the permeation of the cell membrane to K⁺ and Na⁺. Notably, reduction of the intracellular K⁺ concentration was sufficient to activate NLRP3, whereas an increase in intracellular Na⁺ modulated but was not strictly required for inflammasome activation. These results provide a unifying model for the activation of the NLRP3 inflammasome in which a drop in cytosolic K⁺ is the common step that is necessary and sufficient for caspase-1 activation.
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Raúl
authors.initials: R
authors.lastname: Muñoz-Planillo
authors.forename: Peter
authors.initials: P
authors.lastname: Kuffa
authors.forename: Giovanny
authors.initials: G
authors.lastname: Martínez-Colón
authors.forename: Brenna L
authors.initials: BL
authors.lastname: Smith
authors.forename: Thekkelnaycke M
authors.initials: TM
authors.lastname: Rajendiran
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D007113:Immunity, Innate; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009550:Nigericin / Q000494:pharmacology; D052638:Particulate Matter / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D052638:Particulate Matter; D015221:Potassium Channels; D017382:Reactive Oxygen Species; D015222:Sodium Channels; D000255:Adenosine Triphosphate; D020170:Caspase 1; D009550:Nigericin; D011188:Potassium